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Failure of bromocriptine to restore the menstrual cycle in normoprolactinemic post-pill amenorrhea
FERTILITY AND STERIUTY Copyright ~ 1983 The American Fertility Society
Vol. 39, No.2, February 1983 Printed in U.SA.
Failure of bromocriptine to restore the menstrual cycle in normoprolactinemic post-pill amenorrhea
HeIjan J. T. Coelingh Bennink, M.D., Ph.D.* Henk J. van der Steeg, M.D., Ph.D.t Department of Obstetrics and Gynecology, Endocrinological Unit, State University Hospital Academisch Ziekenhuis Utrecht, Utrecht, The Netherlands
Bromocriptine has been reporte:l to be effective in restoring the menstrual cycle in women with normoprolactinemic amenorrhea. 1 In a previous study we observed a 60% success rate in 27 women with normoprolactinemic post-pill amenorrhea (NPPA).2 However, these studies were not performed with double-blind placebo controls. Crosignani et al.a tested bromocriptine in a doubleblind study with matched controls in normoprolactinemic amenorrheic women. They observed no difference in the restoration of the menstrual cycle between the bromocriptine group and the placebo group. However, in this study, women with a history of oral contraceptive (OC) use were excluded. Therefore, it seemed worthwhile to test the efficacy of bromocriptine in women with NPPA in a double-blind placebo-controlled randomized study. PATIENTS AND METHODS SELECTION OF PATIENTS
Twenty-nine patients were selected for the study according to the following criteria: (1) sec-
Received June 8, 1982; revised and accepted September 21, 1982. *Reprint requests: HeIjan J. T. Coelingh Bennink, M.D., Ph.D., Department of Obstetrics and Gynecology, Endocrinological Unit, State University Hospital Academisch Ziekenhuis Utrecht, Catharijnesingel 101, 3500 CG Utrecht, The Netherlands. tPresent address: Stichting Doetinchemse Ziekenhuizen, Doetinchem, The Netherlands. 238
ondary amenorrhea of at least 6 months' duration after discontinuation ofOCs, irrespective of basal levels of estrogens or gonadotropins, except hypergonadotropism; (2) normoprolactinemia (plasma prolactin [PRL] < 0.6 mU/ml); (3) no galactorrhea; (4) no recognizable cause of anovulation in an intensive endocrinologic screening procedure (premature menopause, anorexia nervosa, hyperprolactinemia, and polycystic ovarian disease were excluded by this procedure); (5) no history of or present use of drugs known to interfere with PRL metabolism (except OCs); and (6) informed consent of the patient to participate in the study. TREATMENT SCHEDULE
The study was performed double-blind with placebo controls. Active tablets contained 1.5 mg bromocriptine. The dosage ofbromocriptine was 3 mg (2 tablets) per day. Treatment lasted 12 weeks or was discontinued after the second vaginal bleeding. Follow-up visits were scheduled at 2-week intervals, when measurements of PRL, estradiol (E 2), and progesterone (P) levels were made. All patients kept basal body temperature (BBT) charts and registered any episodes of vaginal bleeding. Ovulation was assumed to have occurred if a biphasic BBT and/or a significant rise in plasma P was noted. PATIENTS
Thirteen women were treated with 3 mg bromocriptine daily for a period of 10 to 12 weeks, and 16 women were treated with a placebo for 9 to 12
Coelingh Bennink and van der Steeg Communications-in-brief
Fertility and Sterility
Table 1. Age, Weight, Menstrual Cycle, Period of Oral Contraceptive Use, and Duration of Amenorrhea in 29 Women with Post-Pill Amenorrhea Treated with Bromocriptine (n = 13) or Placebo (n = 16) Placebo No. of patients 16 Age (yrs) Mean ± SDa 24.3 ± 3.4 Median 24 19-32 Range Weight (kg) 57.8 ± 6.1 Mean ± SD 56.5 Median 48.4-67.8 Range Menstrual cycle before OC use Regular 12 Irregular/oligomenor4 rhea Duration of OC use (mo) 37.7 ± 21.3 Mean ± SD 36 Median Range 6--84 Duration of amenorrhea (mo) 13.6 ± 11.3 Mean ± SD Median 10 Range 6-48 >6 10 > 12 6
Bromocriptine 13 24.5 ± 3.2 25 19-30 54.0 ± 5.6 54.5 44.7-65 8 5 39.4 ± 26.3 33 3-84 12.1 ± 8.2 9 6--36 10 3
aStandard deviation.
weeks. Table 1 summarizes information about age, weight, menstrual cycle before OC use, duration of OC use, and duration of amenorrhea. No significant differences were observed between the two groups. Table 2 contains individual information about duration of OC use, duration of amenorrhea, and plasma PRL levels before treatment. ASSAY METHODS
PRL, E 2 , and P were measured in duplicate in venous blood plasma by a homologous radioimmunoassay (RIA) method. The intraassay coefficients of variation were 7% to 10%. The interassay coefficients of variation were 11% to 12%. RESULTS
Menstruation occurred in 4 of 13 women during treatment with bromocriptine. According to the BBT and/or P levels in the luteal phase, ovulation was likely in one of them, whereas the other three women showed anovulatory bleeding. Vaginal bleeding was reported by 9 of 16 women in the placebo group, and ovulation seemed likely in 8 of them. One woman became pregnant at the first Vol. 39, No.2, February 1983
ovulation. Detailed information about the results of treatment is shown in Table 2. DISCUSSION
According to Corenblum and Taylor,! the return of menses in amenorrheic normoprolactinemic women after treatment with bromocriptine is well documented. However, this documentation is based on noncontrolled studies. The only placebo-controlled study in normoprolactinemic women known to us was performed by Crosignani et a1. 3 They observed no clear difference in the menstrual and ovulatory patterns of placebo and bromocriptine groups. Because Crosignani et a1. 3 excluded women with a history of OC therapy and because our former studies2 , 4 were performed exclusively on women with NPPA but without the obligatory double-blind placebo controls, the effect of bromocriptine in NPPA remained questionable. The results of the placebo-controlled doubleblind study reported in this paper show clearly that bromocriptine has no effect on the restoration of the menstrual cycle in NPPA. It therefore has to be concluded that the results reported in previous papers are placebo effects. Induction of ovulation in unselected groups of anovulatory women is accompanied by a 60% placebo effect. This is in accordance with the 60% placebo effect ofbromocriptine shown in our earlier studies. 2 , 4 Koike et a1. 5 recently reported a 60% success rate of combined bromocriptine and clomiphene treatment in clomiphene-negative normoprolactinemic amenorrheic women; but because this study was not placebo-controlled, it has yet to be proved that this result was also not due to a placebo effect. Evidence is accumulating that a small but significant proportion of cases of post-pill amenorrhea (PPA) may be attributed to previous use of OCs. 6 As has been shown in this paper, there are no arguments for treating women with PPA with bromocriptine because the expected placebo effect was not increased by bromocriptine. SUMMARY
A double-blind placebo-controlled study was performed on 29 women to test the efficacy of bromocriptine in cases of NPPA. Thirteen women were treated with bromocriptine (1.5 mg twice daily) for a period ranging from 10 to 12 weeks.
Coelingh Bennink and van der Steeg Communications-in-brief
239
Table 2. Period of Oral Contraceptive Use, Duration of Amenorrhea, Prolactin Plasma Level Before Treatment, and the Results of BromocriptinelPlacebo Treatment in 29 Women with Post-Pill Amenorrhea Patient no.
Bromocriptine 1 2 3 4 5 6 7 8 9 10 11 12 13 Placebo 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Duration of OCuse
Duration of amenorrhea
mo
ma
18 36 24 84 3 20 72 3 30 72 48 48 54
7 8 11 6 9 7 12 18 17 12 36 6 8
3 5 7 6 6 8 8 12 10 11 5 9 3
72 84 24 42 ? 7 42 31 28 60 30 26 36 6 42 36
10 6 15 7 8 28 9 9 6 10 16 6 6 18 10 48
13 (0.52) 4 (0.16) 10 (0.40) 8 (0.32) 8 (0.32) 8 (0.32) 10 (0.40) 10 (0.40) 7 (0.28) 10 (0.40) 14 (0.56) 7 (0.28) 10 (0.40) 14 (0.56) 9 (0.36) 8 (0.32)
Prolactin plasma Menstrual periods during treatment level in ng/ml
(0.12) (0.20) (0.28) (0.24) (0.24) (0.32) (0.32) (0.48) (0.40) (0.44) (0.20) (0.36) (0.12)
Acknowledgments. We are grateful to Dr. K. Hamersma, Department of Obstetrics and Gynecology of the Oudenrijn Hospital, Utrecht; Dr. P. G. Hart, Department of Obstetrics and Gynecology of the Diakonessenhuis, Utrecht; Dr. L. A. Schellekens, Department of Obstetrics and Gynecology of the de Wever Hospital, Heerlen; Dr. J. M. W. M. Merkus, Department of Obstetrics and Gynecology of the Maria-Hospital, Tilburg; and Dr. H. 't Hart, Department of Obstetrics and Gynecology of the St. Jozefand Geertruiden-Hospital, Deventer, for their cooperation in this study.
240
Ovulation (Ov) or anovulatory bleeding (Anov)
days
(mUlml)
Sixteen women were treated with a placebo (1 tablet twice daily) for 9 to 12 weeks. At least one episode of vaginal bleeding and/or ovulation occurred in 4 of 13 women in the bromocriptine group and in 10 of 16 women in the placebo group. It is concluded that bromocriptine is not effective in the treatment of NPPA.
Treatment period until the first menstruation
0 0 1 0 3 2 0 0 0 1 0 0 0
82
Anov
28 44
Anov Ov
39
Anov
2 38 0 2 74 1 70 0 0 2 63 1 49 0 1 90 1 55 2 47 1 17 0 Conception at first ovulation 0
Ov Ov Ov Ov pv
Anov Ov Ov Ov Ov
REFERENCES 1. Corenblum B, Taylor PJ: A rationale for the use of bromocriptine in patients with amenorrhea and normoprolactinemia. Fertil Steril 34:239, 1980 2. van der Steeg HJ, Coelingh Bennink HJT: The treatment of post-pill amenorrhoea with bromocriptine. Acta Endocrinol (Copenh) 225:170, 1979 3. Crosignani PG, Reschini E, Lombroso GC, Arioso M, Peracchi M: Comparison of placebo and bromocriptine in the treatment of patients with normoprolactinaemic amenorrhoea. Br J Obstet Gynaecol 85:773, 1978 4. van der Steeg HJ, Coelingh Bennink HJT: Bromocriptine for induction of ovulation in normoprolactinaemic postpill anovulation. Lancet 1:502, 1977 5. Koike K, Aono T, Miyake A, Tsutsumi H, Matsumoto K, Kurachi K: Induction of ovulation in patients with normoprolactinemic amenorrhea by combined therapy with bromocriptine and clomiphene. Fertil Steril 35:138, 1981 6. Hull MGR, Bromham DR, Savage PE, Barlow TM, Hughes AO, Jacobs HS: Post-pill amenorrhea: a causal study. Fertil Steril 36:472, 1981
Coelingh Bennink and van der Steeg Communications-in-brief
Fertility and Sterility
Vol. 39, No.2, February 1983 Printed in U.SA.
Failure of bromocriptine to restore the menstrual cycle in normoprolactinemic post-pill amenorrhea
HeIjan J. T. Coelingh Bennink, M.D., Ph.D.* Henk J. van der Steeg, M.D., Ph.D.t Department of Obstetrics and Gynecology, Endocrinological Unit, State University Hospital Academisch Ziekenhuis Utrecht, Utrecht, The Netherlands
Bromocriptine has been reporte:l to be effective in restoring the menstrual cycle in women with normoprolactinemic amenorrhea. 1 In a previous study we observed a 60% success rate in 27 women with normoprolactinemic post-pill amenorrhea (NPPA).2 However, these studies were not performed with double-blind placebo controls. Crosignani et al.a tested bromocriptine in a doubleblind study with matched controls in normoprolactinemic amenorrheic women. They observed no difference in the restoration of the menstrual cycle between the bromocriptine group and the placebo group. However, in this study, women with a history of oral contraceptive (OC) use were excluded. Therefore, it seemed worthwhile to test the efficacy of bromocriptine in women with NPPA in a double-blind placebo-controlled randomized study. PATIENTS AND METHODS SELECTION OF PATIENTS
Twenty-nine patients were selected for the study according to the following criteria: (1) sec-
Received June 8, 1982; revised and accepted September 21, 1982. *Reprint requests: HeIjan J. T. Coelingh Bennink, M.D., Ph.D., Department of Obstetrics and Gynecology, Endocrinological Unit, State University Hospital Academisch Ziekenhuis Utrecht, Catharijnesingel 101, 3500 CG Utrecht, The Netherlands. tPresent address: Stichting Doetinchemse Ziekenhuizen, Doetinchem, The Netherlands. 238
ondary amenorrhea of at least 6 months' duration after discontinuation ofOCs, irrespective of basal levels of estrogens or gonadotropins, except hypergonadotropism; (2) normoprolactinemia (plasma prolactin [PRL] < 0.6 mU/ml); (3) no galactorrhea; (4) no recognizable cause of anovulation in an intensive endocrinologic screening procedure (premature menopause, anorexia nervosa, hyperprolactinemia, and polycystic ovarian disease were excluded by this procedure); (5) no history of or present use of drugs known to interfere with PRL metabolism (except OCs); and (6) informed consent of the patient to participate in the study. TREATMENT SCHEDULE
The study was performed double-blind with placebo controls. Active tablets contained 1.5 mg bromocriptine. The dosage ofbromocriptine was 3 mg (2 tablets) per day. Treatment lasted 12 weeks or was discontinued after the second vaginal bleeding. Follow-up visits were scheduled at 2-week intervals, when measurements of PRL, estradiol (E 2), and progesterone (P) levels were made. All patients kept basal body temperature (BBT) charts and registered any episodes of vaginal bleeding. Ovulation was assumed to have occurred if a biphasic BBT and/or a significant rise in plasma P was noted. PATIENTS
Thirteen women were treated with 3 mg bromocriptine daily for a period of 10 to 12 weeks, and 16 women were treated with a placebo for 9 to 12
Coelingh Bennink and van der Steeg Communications-in-brief
Fertility and Sterility
Table 1. Age, Weight, Menstrual Cycle, Period of Oral Contraceptive Use, and Duration of Amenorrhea in 29 Women with Post-Pill Amenorrhea Treated with Bromocriptine (n = 13) or Placebo (n = 16) Placebo No. of patients 16 Age (yrs) Mean ± SDa 24.3 ± 3.4 Median 24 19-32 Range Weight (kg) 57.8 ± 6.1 Mean ± SD 56.5 Median 48.4-67.8 Range Menstrual cycle before OC use Regular 12 Irregular/oligomenor4 rhea Duration of OC use (mo) 37.7 ± 21.3 Mean ± SD 36 Median Range 6--84 Duration of amenorrhea (mo) 13.6 ± 11.3 Mean ± SD Median 10 Range 6-48 >6 10 > 12 6
Bromocriptine 13 24.5 ± 3.2 25 19-30 54.0 ± 5.6 54.5 44.7-65 8 5 39.4 ± 26.3 33 3-84 12.1 ± 8.2 9 6--36 10 3
aStandard deviation.
weeks. Table 1 summarizes information about age, weight, menstrual cycle before OC use, duration of OC use, and duration of amenorrhea. No significant differences were observed between the two groups. Table 2 contains individual information about duration of OC use, duration of amenorrhea, and plasma PRL levels before treatment. ASSAY METHODS
PRL, E 2 , and P were measured in duplicate in venous blood plasma by a homologous radioimmunoassay (RIA) method. The intraassay coefficients of variation were 7% to 10%. The interassay coefficients of variation were 11% to 12%. RESULTS
Menstruation occurred in 4 of 13 women during treatment with bromocriptine. According to the BBT and/or P levels in the luteal phase, ovulation was likely in one of them, whereas the other three women showed anovulatory bleeding. Vaginal bleeding was reported by 9 of 16 women in the placebo group, and ovulation seemed likely in 8 of them. One woman became pregnant at the first Vol. 39, No.2, February 1983
ovulation. Detailed information about the results of treatment is shown in Table 2. DISCUSSION
According to Corenblum and Taylor,! the return of menses in amenorrheic normoprolactinemic women after treatment with bromocriptine is well documented. However, this documentation is based on noncontrolled studies. The only placebo-controlled study in normoprolactinemic women known to us was performed by Crosignani et a1. 3 They observed no clear difference in the menstrual and ovulatory patterns of placebo and bromocriptine groups. Because Crosignani et a1. 3 excluded women with a history of OC therapy and because our former studies2 , 4 were performed exclusively on women with NPPA but without the obligatory double-blind placebo controls, the effect of bromocriptine in NPPA remained questionable. The results of the placebo-controlled doubleblind study reported in this paper show clearly that bromocriptine has no effect on the restoration of the menstrual cycle in NPPA. It therefore has to be concluded that the results reported in previous papers are placebo effects. Induction of ovulation in unselected groups of anovulatory women is accompanied by a 60% placebo effect. This is in accordance with the 60% placebo effect ofbromocriptine shown in our earlier studies. 2 , 4 Koike et a1. 5 recently reported a 60% success rate of combined bromocriptine and clomiphene treatment in clomiphene-negative normoprolactinemic amenorrheic women; but because this study was not placebo-controlled, it has yet to be proved that this result was also not due to a placebo effect. Evidence is accumulating that a small but significant proportion of cases of post-pill amenorrhea (PPA) may be attributed to previous use of OCs. 6 As has been shown in this paper, there are no arguments for treating women with PPA with bromocriptine because the expected placebo effect was not increased by bromocriptine. SUMMARY
A double-blind placebo-controlled study was performed on 29 women to test the efficacy of bromocriptine in cases of NPPA. Thirteen women were treated with bromocriptine (1.5 mg twice daily) for a period ranging from 10 to 12 weeks.
Coelingh Bennink and van der Steeg Communications-in-brief
239
Table 2. Period of Oral Contraceptive Use, Duration of Amenorrhea, Prolactin Plasma Level Before Treatment, and the Results of BromocriptinelPlacebo Treatment in 29 Women with Post-Pill Amenorrhea Patient no.
Bromocriptine 1 2 3 4 5 6 7 8 9 10 11 12 13 Placebo 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Duration of OCuse
Duration of amenorrhea
mo
ma
18 36 24 84 3 20 72 3 30 72 48 48 54
7 8 11 6 9 7 12 18 17 12 36 6 8
3 5 7 6 6 8 8 12 10 11 5 9 3
72 84 24 42 ? 7 42 31 28 60 30 26 36 6 42 36
10 6 15 7 8 28 9 9 6 10 16 6 6 18 10 48
13 (0.52) 4 (0.16) 10 (0.40) 8 (0.32) 8 (0.32) 8 (0.32) 10 (0.40) 10 (0.40) 7 (0.28) 10 (0.40) 14 (0.56) 7 (0.28) 10 (0.40) 14 (0.56) 9 (0.36) 8 (0.32)
Prolactin plasma Menstrual periods during treatment level in ng/ml
(0.12) (0.20) (0.28) (0.24) (0.24) (0.32) (0.32) (0.48) (0.40) (0.44) (0.20) (0.36) (0.12)
Acknowledgments. We are grateful to Dr. K. Hamersma, Department of Obstetrics and Gynecology of the Oudenrijn Hospital, Utrecht; Dr. P. G. Hart, Department of Obstetrics and Gynecology of the Diakonessenhuis, Utrecht; Dr. L. A. Schellekens, Department of Obstetrics and Gynecology of the de Wever Hospital, Heerlen; Dr. J. M. W. M. Merkus, Department of Obstetrics and Gynecology of the Maria-Hospital, Tilburg; and Dr. H. 't Hart, Department of Obstetrics and Gynecology of the St. Jozefand Geertruiden-Hospital, Deventer, for their cooperation in this study.
240
Ovulation (Ov) or anovulatory bleeding (Anov)
days
(mUlml)
Sixteen women were treated with a placebo (1 tablet twice daily) for 9 to 12 weeks. At least one episode of vaginal bleeding and/or ovulation occurred in 4 of 13 women in the bromocriptine group and in 10 of 16 women in the placebo group. It is concluded that bromocriptine is not effective in the treatment of NPPA.
Treatment period until the first menstruation
0 0 1 0 3 2 0 0 0 1 0 0 0
82
Anov
28 44
Anov Ov
39
Anov
2 38 0 2 74 1 70 0 0 2 63 1 49 0 1 90 1 55 2 47 1 17 0 Conception at first ovulation 0
Ov Ov Ov Ov pv
Anov Ov Ov Ov Ov
REFERENCES 1. Corenblum B, Taylor PJ: A rationale for the use of bromocriptine in patients with amenorrhea and normoprolactinemia. Fertil Steril 34:239, 1980 2. van der Steeg HJ, Coelingh Bennink HJT: The treatment of post-pill amenorrhoea with bromocriptine. Acta Endocrinol (Copenh) 225:170, 1979 3. Crosignani PG, Reschini E, Lombroso GC, Arioso M, Peracchi M: Comparison of placebo and bromocriptine in the treatment of patients with normoprolactinaemic amenorrhoea. Br J Obstet Gynaecol 85:773, 1978 4. van der Steeg HJ, Coelingh Bennink HJT: Bromocriptine for induction of ovulation in normoprolactinaemic postpill anovulation. Lancet 1:502, 1977 5. Koike K, Aono T, Miyake A, Tsutsumi H, Matsumoto K, Kurachi K: Induction of ovulation in patients with normoprolactinemic amenorrhea by combined therapy with bromocriptine and clomiphene. Fertil Steril 35:138, 1981 6. Hull MGR, Bromham DR, Savage PE, Barlow TM, Hughes AO, Jacobs HS: Post-pill amenorrhea: a causal study. Fertil Steril 36:472, 1981
Coelingh Bennink and van der Steeg Communications-in-brief
Fertility and Sterility